MICAL1在乳腺癌细胞侵袭性伪足形成和转移中的作用及机制研究

恶性肿瘤细胞突破细胞外基质是实现其转移的重要步骤，而恶性肿瘤细胞侵袭性伪足的形成是其突破细胞外基质的前提和关键。已有的研究表明，MICAL1是新近发现的具有调控肌动蛋白微丝重构作用的蛋白，在乳腺癌细胞迁移和浸润过程中具有极其重要的作用，然而其是否调控侵袭性伪足形成及确切分子机制目前尚未明确。本工作将致力于阐明：（1）MICAL1是否通过氧化肌动蛋白，进而调控微丝骨架重构和侵袭性伪足形成？（2）NEDD9是否为调控MICAL1微丝重构功能的关键分子？（3）NEDD9是否通过激活MICAL1重构微丝骨架，进而调控乳腺癌细胞侵袭性伪足形成及细胞转移？本研究目标的完成将阐明MICAL1调控乳腺癌细胞侵袭性伪足形成的确切分子机制，在更深层次揭示乳腺癌细胞转移的确切分子机制。

Several key stages of cancer cell directional migration are thought to involve ECM degradation.In recent years, subcellular protrusions known as invadopodia have been shown to be critical for ECM degradation. MICAL1, a new discovered actin cytoskeleton regulator, is up-regulated in multiple cancers including breast cancer. Although evidence suggests that MICAL1 functions to promote breast cancer cell migration and invasion, the role of MICAL1 in invadopodia dynamics is unknown. The priorities of our work are to elucidate:（1）Whether MICAL1 promotes actin filaments re-orgnization and invadopodia formation by oxidizing actin microfilaments?（2）Whether NEDD9 is a vital regulator of MICAL1 function and required specifically for actin dynamics at the leading edge?（3）Whether NEDD9 co-localizes and binds to MICAL1 within plasma membrane protrusion, that leads to the formation of invadopodia and invasion of breast cancer cells? It may be a novel mechanism that both of NEDD9 and MICAL1 participate in actin filaments dynamics and regulate consequently invadopodia formation, which could be a new therapeutic target against breast cancer cell metastasis.